The Section for the study of gastrointestinal tumors is divided into two broad areas that include the development of strategies for the treatment of solid tumors, in particular, those arising from the gastrointestinal tract, and the development of therapies for the treatment of opportunistic infections in patients with AIDS. The antineoplastic investigations revolve around the development of a complete understanding of the mechanisms of action and the mechanisms of resistance to the antimetabolite class of antineoplastic agents, specifically, 5-fluorouracil and methotrexate. The central focus of this area is to improve the therapy of solid tumors by 1) modulating the activity of the available antimetabolite agents in an effort to improve activity and circumvent resistance mechanisms defined from both preclinical and clinical investigations 2) enhancing the dose intensity of antimetabolite agents through use of biologic agents such as interferon and colony stimulating factors and 3) investigating the activity and mechanisms of action and resistance of novel agents for the treatment of gastrointestinal malignancies. In addition, we are investigating the growth factor requirements for colorectal carcinoma and adenoma cells in an attempt to characterize and interfere with these growth requirements. By investigating the progression from adenoma to carcinoma we hope to understand how various growth factors may be involved in malignant transformation with the ultimate goal of preventing such transformation. The investigations of therapies for opportunistic infections is focused on the interactions of antifolate agents on the metabolic pathways in toxoplasma gondii, pneumocystis carinii and cryptosporidium. In addition to the use of basic biochemical technologies, we are using the tools of molecular biology to clone, sequence and express clinically relevant target enzymes for characterization and as an aide in the search for new therapeutic agents.